Approximately 1.8 million abdominal surgeries are performed in United States each year. Postoperative adhesions occur in 67-93% of the people who undergo these abdominal surgeries. In the United States, the annual expense of removing abdominal adhesions is estimated to be in excess of 2 billion dollars. Worldwide total surgical procedures are as follows; Lumbar (800,000), Tendon/Nerve (500,000), Abdominal (2 million), Pelvic (2.6 million, Implants (2 million), and cardiac (2 million). All of these surgical procedures can cause the formation of extensive post-operative adhesions. While adhesions are inevitable in several types of surgeries, good surgical technique combined with therapeutic agents, such as the invention claimed in this application, can greatly reduce the likelihood and/or extent of adhesion formation. Detrimental and painful adhesions can also form as a result of non-surgical physical injury. In the case of severe physical injury, adhesions can form at the wound site, during wound healing.
In both the cases of surgery and non-surgical physical injury, organs or tissues attach to each other via scar tissue and introduce clinical problems. While the formation of scar tissue is part of the normal healing process and is required for proper wound healing, in some cases the scar tissue overgrows. When the scar tissue proliferates beyond the boundaries of the wound, this extraneous scar tissue creates adhesions between otherwise healthy tissues. These adhesions are often painful and may lead to other problems. In extreme cases, adhesions can lead to intestinal obstruction, female infertility, organ failure, paralysis and even death. Formation of such adhesions restrict the normal mobility and function of affected body parts and are therefore named as complications of almost all major surgical procedures and is frequently observed after serious physical injury. The compound of this invention is a new composition of matter and can be used in a variety of surgeries, and as part of treatment for non-surgical physical injury, where inhibition of adhesion formation and improved wound healing is required.
The use of Dextran-70, Lactated Ringers, Hyaluronic acid, cellulosic, crosslinked hyaluronic acids, glycosaminoglycans, and synthetic & natural polymers have been used with some success.1 Additionally, the use of drugs such as tissue plasminogen activator, tolmetin, ibuprofen, dexamethasone, and verapamil in preventing adhesions has also been reported. A few of the clinical applications include use in surgeries of the lumbar region, tendons, peripheral nerves, and surgeries which apply implants. Adhesion reducing compounds and devices can be used to prevent pelvic adhesions, abdominal adhesions, cardiac adhesions, ophthalmic adhesions, and adhesions forming in the sinuses. A number of animal models are available to evaluate the effect of compounds for a particular indication of interest. For example, these models include laminectomy in rats and rabbits, flexor tenolysis in rabbits and chickens, sciatic nerve neurolysis in rats, breast implants in rabbits, steronotomy in rabbits, cardiac procedures in rats and rabbits, and fallopian tube procedures in rats and rabbits. Bowl adhesions can be induced in rats and rabbits. The uterine abrasion model can be used in rats and rabbits. Use of these models for novel compound evaluation has been accepted within the art. In these models, reduction in the development of scar tissue is evidence of a reduction in the formation of adhesions. There exists significant association between scar tissue formation and adhesion formation. It is known within the medical profession that reduction in the formation of adhesions and excessive scar tissue leads to improved surgical outcome, and improved recovery from physical injury.
Large numbers of cases have been reported that deal with the adhesions as a result of surgery. While different types surgical procedures lead to adhesions of various severities and consequences, depending on the extent and location of the procedure, the outcome of any surgical procedure can be improved if adhesions are prevented. Improved surgical outcomes reduce the healthcare costs, and indirect costs, of post-operative recovery. After a patient undergoes back surgery, severe adhesions are often reported. The formation of these adhesions leads to severe back pain and increases the difficulty of repeated surgery. Both, lumbar laminectomy and discectomy surgeries cause recurrent radicular pain.
Dextran Sulfate only has been used in reducing surgical adhesions with limited success in human patients. Dextran sulfate alone does not prevent the accumulation of cellular debris which results from the destruction of platelets. Destruction of platelets occurs as a consequence of platelet aggregation. Agents which prevent platelet aggregation can thus prevent platelet destruction and the corresponding accumulation of cellular debris from destroyed platelet cells. The new compound, claimed in this invention, was prepared by covalent conjugation of Tirofiban (which prevents the formation of platelet aggregates) to Dextran Sulfate. This new conjugate compound prevents 3T3 cell proliferation, glioma cell proliferation, and platelet break-down. The invention is the first anti-adhesion therapeutic which prevents the formation of excessive scar tissue while also preventing platelet aggregation, platelet destruction, and accumulation of cellular debris resulting from platelet destruction.
A newly developed embodiment of the claimed invention consists of an anionic carbohydrate (such as dextran sulfate) paired with an anti-platelet aggregation compound (such as Tirofiban), in a non-covalently bound salt formation.